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. 1992 Nov;36(11):2403–2407. doi: 10.1128/aac.36.11.2403

Optimal aminoglycoside dosing regimen for penicillin-tobramycin synergism in experimental Streptococcus adjacens endocarditis.

A Saleh-Mghir 1, A C Cremieux 1, J M Vallois 1, M Muffat-Joly 1, C Devine 1, C Carbon 1
PMCID: PMC284343  PMID: 1489184

Abstract

The combination of penicillin and aminoglycoside is the recommended therapy for endocarditis caused by nutritionally variant streptococci (NVS). However, the optimal aminoglycoside dosing regimen remains controversial. We compared the efficacies of four regimens of tobramycin alone or combined with procaine penicillin in the therapy of rabbits with endocarditis caused by Streptococcus adjacens, a new species of NVS. Animals were injected intramuscularly for 4 days with procaine penicillin (150,000 U/kg of body weight twice daily) or tobramycin at a low dose (3 mg/kg every 24 h) or a high dose (12 mg/kg every 24 h) either once or three times daily (t.i.d.) alone or in combination with procaine penicillin. Additional groups of animals were treated with the combination regimens for a shorter period of time (2 days) in order to demonstrate a possible difference in the rapidity of efficacy between the regimens. The MICs and MBCs were 0.015 and 1 micrograms/ml and 8 and 16 micrograms/ml for penicillin and tobramycin, respectively. The mean peak tobramycin levels in plasma were 2.4 +/- 1.3 (1 mg/kg t.i.d.), 5.4 +/- 3.7 (4 mg/kg t.i.d.), and 25 +/- 9.3 (12 mg/kg once daily). The mean penicillin levels in serum were always above the MIC. In vitro kill curves plotted at the time that peak concentrations were reached in plasma showed a concentration-dependent killing effect of tobramycin alone but not in combination with penicillin. In vivo, low-dose tobramycin was significantly less effective than the high dose. Results for the combinations of the different dosing regimens of tobramycin with procaine penicillin were not significantly different. Our results suggest that (i) against susceptible strains of streptococci, aminoglycoside alone exhibits a concentration-dependent killing effect both in vitro and in vivo; (ii) against NVS strains, combinations of penicillin and high- or low-dose tobramycin are equally effective; and (iii) aminoglycoside given once daily or at a low dose t.i.d. with penicillin could be a cost-effective alternative with reduced toxic risk for patients with NVS endocarditis when the bacteria are susceptible to the killing activities of both compounds.

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Selected References

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  1. Bisno A. L., Dismukes W. E., Durack D. T., Kaplan E. L., Karchmer A. W., Kaye D., Rahimtoola S. H., Sande M. A., Sanford J. P., Watanakunakorn C. Antimicrobial treatment of infective endocarditis due to viridans streptococci, enterococci, and staphylococci. JAMA. 1989 Mar 10;261(10):1471–1477. [PubMed] [Google Scholar]
  2. Blaser J., Stone B. B., Zinner S. H. Efficacy of intermittent versus continuous administration of netilmicin in a two-compartment in vitro model. Antimicrob Agents Chemother. 1985 Mar;27(3):343–349. doi: 10.1128/aac.27.3.343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bouvet A., Cremieux A. C., Contrepois A., Vallois J. M., Lamesch C., Carbon C. Comparison of penicillin and vancomycin, individually and in combination with gentamicin and amikacin, in the treatment of experimental endocarditis induced by nutritionally variant streptococci. Antimicrob Agents Chemother. 1985 Nov;28(5):607–611. doi: 10.1128/aac.28.5.607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bouvet A., van de Rijn I., McCarty M. Nutritionally variant streptococci from patients with endocarditis: growth parameters in a semisynthetic medium and demonstration of a chromophore. J Bacteriol. 1981 Jun;146(3):1075–1082. doi: 10.1128/jb.146.3.1075-1082.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carey R. B., Brause B. D., Roberts R. B. Antimicrobial therapy of vitamin B6-dependent streptococcal endocarditis. Ann Intern Med. 1977 Aug;87(2):150–154. doi: 10.7326/0003-4819-87-2-150. [DOI] [PubMed] [Google Scholar]
  6. Cremieux A. C., Maziere B., Vallois J. M., Ottaviani M., Azancot A., Raffoul H., Bouvet A., Pocidalo J. J., Carbon C. Evaluation of antibiotic diffusion into cardiac vegetations by quantitative autoradiography. J Infect Dis. 1989 May;159(5):938–944. doi: 10.1093/infdis/159.5.938. [DOI] [PubMed] [Google Scholar]
  7. Fantin B., Carbon C. Importance of the aminoglycoside dosing regimen in the penicillin-netilmicin combination for treatment of Enterococcus faecalis-induced experimental endocarditis. Antimicrob Agents Chemother. 1990 Dec;34(12):2387–2391. doi: 10.1128/aac.34.12.2387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gerber A. U., Brugger H. P., Feller C., Stritzko T., Stalder B. Antibiotic therapy of infections due to Pseudomonas aeruginosa in normal and granulocytopenic mice: comparison of murine and human pharmacokinetics. J Infect Dis. 1986 Jan;153(1):90–97. doi: 10.1093/infdis/153.1.90. [DOI] [PubMed] [Google Scholar]
  9. Gilbert D. N. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother. 1991 Mar;35(3):399–405. doi: 10.1128/aac.35.3.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Henry N. K., Wilson W. R., Roberts R. B., Acar J. F., Geraci J. E. Antimicrobial therapy of experimental endocarditis caused by nutritionally variant viridans group streptococci. Antimicrob Agents Chemother. 1986 Sep;30(3):465–467. doi: 10.1128/aac.30.3.465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hessen M. T., Pitsakis P. G., Levison M. E. Postantibiotic effect of penicillin plus gentamicin versus Enterococcus faecalis in vitro and in vivo. Antimicrob Agents Chemother. 1989 May;33(5):608–611. doi: 10.1128/aac.33.5.608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kapusnik J. E., Hackbarth C. J., Chambers H. F., Carpenter T., Sande M. A. Single, large, daily dosing versus intermittent dosing of tobramycin for treating experimental pseudomonas pneumonia. J Infect Dis. 1988 Jul;158(1):7–12. doi: 10.1093/infdis/158.1.7. [DOI] [PubMed] [Google Scholar]
  13. Miller M. H., el-Sokkary M. A., Feinstein S. A., Lowy F. D. Penicillin-induced effects on streptomycin uptake and early bactericidal activity differ in viridans group and enterococcal streptococci. Antimicrob Agents Chemother. 1986 Nov;30(5):763–768. doi: 10.1128/aac.30.5.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Moellering R. C., Jr, Weinberg A. N. Studies on antibiotic syngerism against enterococci. II. Effect of various antibiotics on the uptake of 14 C-labeled streptomycin by enterococci. J Clin Invest. 1971 Dec;50(12):2580–2584. doi: 10.1172/JCI106758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Moore R. D., Lietman P. S., Smith C. R. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987 Jan;155(1):93–99. doi: 10.1093/infdis/155.1.93. [DOI] [PubMed] [Google Scholar]
  16. Murray P. R., Niles A. C. Inactivation of penicillins by Thiol broth. J Clin Microbiol. 1982 Nov;16(5):982–984. doi: 10.1128/jcm.16.5.982-984.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Perlman B. B., Freedman L. R. Experimental endocarditis. II. Staphylococcal infection of the aortic valve following placement of a polyethylene catheter in the left side of the heart. Yale J Biol Med. 1971 Oct;44(2):206–213. [PMC free article] [PubMed] [Google Scholar]
  18. Reyes M. P., Lerner A. M. Current problems in the treatment of infective endocarditis due to Pseudomonas aeruginosa. Rev Infect Dis. 1983 Mar-Apr;5(2):314–321. doi: 10.1093/clinids/5.2.314. [DOI] [PubMed] [Google Scholar]
  19. Roberts R. B., Krieger A. G., Schiller N. L., Gross K. C. Viridans streptococcal endocarditis: the role of various species, including pyridoxal-dependent streptococci. Rev Infect Dis. 1979 Nov-Dec;1(6):955–966. doi: 10.1093/clinids/1.6.955. [DOI] [PubMed] [Google Scholar]
  20. Sullam P. M., Täuber M. G., Hackbarth C. J., Sande M. A. Antimicrobial activity of gentamicin in experimental enterococcal endocarditis. Antimicrob Agents Chemother. 1985 Feb;27(2):224–226. doi: 10.1128/aac.27.2.224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Vogelman B., Gudmundsson S., Leggett J., Turnidge J., Ebert S., Craig W. A. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis. 1988 Oct;158(4):831–847. doi: 10.1093/infdis/158.4.831. [DOI] [PubMed] [Google Scholar]
  22. Weinstein A. J., Moellering R. C., Jr Penicillin and gentamicin therapy for enterococcal infections. JAMA. 1973 Feb 26;223(9):1030–1032. [PubMed] [Google Scholar]
  23. Wright A. J., Wilson W. R., Matsumoto J. Y., Washington J. A., 2nd, Geraci J. E. Influence of gentamicin dose size on the efficacies of combinations of gentamicin and penicillin in experimental streptomycin-resistant enterococcal endocarditis. Antimicrob Agents Chemother. 1982 Dec;22(6):972–975. doi: 10.1128/aac.22.6.972. [DOI] [PMC free article] [PubMed] [Google Scholar]

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